US5124158A - Transdermal antisecretory agents for gastrointestinal disease - Google Patents

Transdermal antisecretory agents for gastrointestinal disease Download PDF

Info

Publication number
US5124158A
US5124158A US07/623,884 US62388490A US5124158A US 5124158 A US5124158 A US 5124158A US 62388490 A US62388490 A US 62388490A US 5124158 A US5124158 A US 5124158A
Authority
US
United States
Prior art keywords
transdermal
compound
methyl
phx
methoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US07/623,884
Inventor
Mary J. Ruwart
Wha B. Im
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Upjohn Co filed Critical Upjohn Co
Assigned to UPJOHN COMPANY, THE reassignment UPJOHN COMPANY, THE ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: IM, WHA B.
Assigned to UPJOHN COMPANY, THE reassignment UPJOHN COMPANY, THE ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: RUWART, MARY J.
Application granted granted Critical
Publication of US5124158A publication Critical patent/US5124158A/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention is directed toward the treatment of gastrointestinal disease through a transdermally administered antisecretory agent.
  • Antisecretory agents shown to be useful for transdermal administration are substituted 2-pyridylmethylthio- and sulfinyl-benzimidazoles and omeprazole.
  • gastric acid secretion is by the inhibition of gastric acid secretion.
  • gastric acid secretion can result in erosion of the epithelial cells with consequent inflammation and ulceration.
  • Prevention and healing of such untoward gastric acid-induced effects can be achieved by the administration of a pharmacological agent which effectively inhibits gastric acid secretion.
  • Suitable agents such as substituted 2-pyridylmethylthio- and sulfinyl-benzimidazoles which are described in U.S. Pat. No. 4,575,554 and are herein incorporated by reference.
  • Omeprazole is another compound known to be effective for the inhibition of gastric acid secretion which is described in U.S. Pat. No. 4,255,431 herein incorporated by reference.
  • Another important aspect to the prevention or treatment of gastrointestinal disease is the continuous, rather than intermittant, inhibition of gastric acid. It is therefore desirable to administer the drugs in a slow continuous fashion over a long period of time such that excess gastric acid secretion is minimized to prevent gastrointestinal disease. Another important consideration is ease of administration and comfort.
  • U.S. Pat. No. 4,575,554 discloses that a continuous inhibition of acid can be achieved by administering a single dose of these compounds subcutaneously. Until this time, subcutaneous administration of this class of compounds was the only choice when a long duration of action (several days or weeks) is desired with a single dose. Unfortunately, subcutaneous injection are not comfortable and sometimes can cause irritation to the surrounding tissue. Also, in the event of toxicity problems removal is difficult.
  • U.S. Pat. No. 4,575,554 discloses the oral and parenteral administration of substituted 2-pyridylmethylthio- and sulfinyl-benzimidazoles for the treatment of gastrointestinal diseases.
  • U.S. Pat. No. 4,255,431 discloses a method and composition including omeprazole for inhibiting gastric acid secretion.
  • the present invention is directed toward a method and transdermal composition for inhibiting the secretion of gastric acid for prevention or treatment of gastrointestinal disease comprising the application to the skin of a mammal, including humans, a therapeutically effective amount of a compound of formula I ##STR1## wherein X is
  • R 5 is (C 1 -C 4 )alkyl, (C 1 -C 4 )alkenyl, PhX, --CH 2 PhX, or (C 3 -C 10 )cycloalkyl, wherein "PhX” is phenyl substituted by zero to 3 of the following: (C 1 -C 4 )alkyl, chloro, fluoro, bromo, nitro, trifluoromethyl, or OR 3 ; and
  • R 3 and R 4 are the same or different and are
  • Preferred compounds derived from Formula 1 are 2-(4-ethylthio-3-methylpyridin-2-yl methyl)sulfinyl-benzimidazole and omeprazole.
  • Omeprazole is where X is ⁇ S ⁇ O, R 1 and R 2 are methoxy and R 3 and R 4 are methyl.
  • the compound is dissolved in a transdermal vehicle in an amount of from about 1 to about 300 mg/dose.
  • the dissolved compound can then be applied to the skin of a mammal, preferably a human being, to be absorbed through the skin such that the (H + -K + ) ATPase enzyme responsible for gastric acid secretion is inhibited.
  • the present invention relates to the effective transdermal administration of substituted 2-pyridylmethylthio- and sulfinyl-benzimidazoles, omeprazole or a pharmaceutically acceptable salt thereof for inhibition of gastric acid secretion.
  • the gastric acid secretion is controlled by inhibiting gastric (H + -K + ) ATPase activity.
  • the 2-pyridylmethylthio- and sulfinyl- benzimidazole compounds are described in U.S. Pat. No. 4,575,554 herein incorporated by reference.
  • the omeprazole compound is described in U.S. Pat. No. 4,255,431 herein incorporated by reference.
  • X is ⁇ S, or ⁇ S ⁇ O
  • R 1 is hydrogen, methyl, methoxy, or trifluoromethyl
  • R 2 is methoxy or --SR 5 wherein R 5 is (C 1 -C 4 )alkyl, (C 1 -C 4 )alkenyl, PhX, --CH 2 PhX or (C 3 -C 10 ) cycloalkyl, wherein "PhX” is phenyl substituted by zero to 3 of the following: (C 1 -C 4 )alkyl, chloro, fluoro, bromo, nitro, trifluoromethyl, or OR 3 ; and R 3 and R 4 are the same or different and are hydrogen, or (C 1 -C 4 )alkyl.
  • a preferred compound from this family is 2-(4-ethylthio-3-methylpyridin-2-yl methyl)sulfinyl-benzimidazole and omeprazole which is when X is ⁇ S ⁇ O, R 1 and R 2 are methoxy and R 3 and R 4 are methyl.
  • transdermal vehicle such as a cream, gel, paste or liquid which are generally known in the art for transdermal use.
  • Typical transdermal compounds are polyethylene glycol, propylene glycol, triacetin, propylcarbonate, ethanol and isopropyl myristate.
  • the compounds can also be applied to porous or other material suitable for preparing a transdermal patch which can be worn by the patient.
  • transdermal vehicles are generally well-known in the pharmaceutical industry and therefore will not be discussed in detail.
  • the compounds are transdermally applied in a therapeutically effective amount to inhibit gastric acid secretion.
  • the amount is from about 1 to about 300 mg/dosage, preferably about 100 to about 200 mg/dosage.
  • the amount used in the transdermal vehicle is greatly in excess of the amount actually transferred into the body.
  • a typical cross-over rate is generally much less than the available drug present in the transdermal vehicle. The dosage is of course dependent upon the patient and diagnosed condition.
  • the subject compounds were dissolved in dimethyl sulfoxide (DMSO) and applied to the backs of rats and onto the ears of rabbits. The animals were allowed to rest for varying amounts of time and then the inhibition of (H + -K + ) ATPase, the enzyme responsible for gastric acid secretion, was measured. The results indicated that the compounds were absorbed such that (H + -K + ) ATPase was inhibited.
  • DMSO dimethyl sulfoxide
  • mucosa from the fundic region was removed by blunt dissection and minced with scissors. 2.5 g of the minced tissue was placed in 25 ml of buffer containing 250 mM sucrose, 2 mM MgCl 2 , 1 mM EGTA, and 2 mM Hepes/Tris, pH 7.4. The tissues were then prepared as described for the rat gastric mucosa.
  • Transdermal treatment with the subject compound reduced (H + -K + ) ATPase activity 60-65% from control. Activity did not change with time.
  • the rats were prepared as described in Example 1 and fasted overnight. The same compound as in Example 1 was applied at 0, 100 or 200 mg/kg. Additional volumes (100 ⁇ l) of DMSO were spread over the treatment area one time (after two hours) or four times (after one, two, three and four hours). The animals were evaluated 5 hours after the initial dose for determination of (H + -K + ) ATPase activity.
  • the transdermal treatment (100 mg/kg) reduced (H + -K + ) ATPase activity 65% from control.
  • Additional applications of DMSO (four wipes) reduced the activity of the same dose an additional 16%.
  • a 200 mg/kg dose with one wipe of DMSO after two hours reduced the (H + -K + ) ATPase activity by 72%.
  • the additional applications of DMSO were more effective (81%) than a single application at twice the dosage (200 mg/kg).
  • Rats were prepared as described in Example 1 and fasted overnight. The same compound as used in Example 1 was applied at 0, 25, 50, or 100 mg/kg. Additional volumes (100 ⁇ l) of DMSO were spread over the treatment area after 2, 5, and 7 hours. The animals were evaluated 24 hours after the initial dose for determination of (H + -K + ) ATPase activity.
  • Example 2 Male, New Zealand White rabbits were fasted overnight without water in their cages prior to treatment. The same compound as used in Example 1 was applied at 0 or 100 mg/kg in divided doses (1/2 to each ear) to naive rabbit ears. The rabbits received an additional application of DMSO to the treatment area after 1, 3, 5, 7, 24 and 25 hrs. The rabbits were evaluated 30 hrs after the initial dose for determination of (H + -K + ) ATPase activity.
  • transdermal application of the subject compounds is effective for reducing (H + -K + ) ATPase activity. Also, the effect remains long lasting when applied and no signs of irritation were apparent.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Materials For Medical Uses (AREA)

Abstract

A method for the treatment of gastrointestinal disease through a transdermally administered antisecretory agent. Antisecretory agents useful for transdermal administration are substituted 2-pyridylmethylthio- and sulfinyl-benzimidazoles and omeprazole.

Description

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
This application is the national phase of international application PCT/US89/01757.
BACKGROUND OF THE INVENTION
The present invention is directed toward the treatment of gastrointestinal disease through a transdermally administered antisecretory agent. Antisecretory agents shown to be useful for transdermal administration are substituted 2-pyridylmethylthio- and sulfinyl-benzimidazoles and omeprazole.
One means for preventing or treating gastrointestinal diseases, specifically gastric and duodenal ulcers, is by the inhibition of gastric acid secretion. In situations where the integrity of the gastric mucosal barrier is compromised, gastric acid secretion can result in erosion of the epithelial cells with consequent inflammation and ulceration. Prevention and healing of such untoward gastric acid-induced effects can be achieved by the administration of a pharmacological agent which effectively inhibits gastric acid secretion.
Various effective agents are known such as substituted 2-pyridylmethylthio- and sulfinyl-benzimidazoles which are described in U.S. Pat. No. 4,575,554 and are herein incorporated by reference. Omeprazole is another compound known to be effective for the inhibition of gastric acid secretion which is described in U.S. Pat. No. 4,255,431 herein incorporated by reference.
Another important aspect to the prevention or treatment of gastrointestinal disease is the continuous, rather than intermittant, inhibition of gastric acid. It is therefore desirable to administer the drugs in a slow continuous fashion over a long period of time such that excess gastric acid secretion is minimized to prevent gastrointestinal disease. Another important consideration is ease of administration and comfort.
U.S. Pat. No. 4,575,554 discloses that a continuous inhibition of acid can be achieved by administering a single dose of these compounds subcutaneously. Until this time, subcutaneous administration of this class of compounds was the only choice when a long duration of action (several days or weeks) is desired with a single dose. Unfortunately, subcutaneous injection are not comfortable and sometimes can cause irritation to the surrounding tissue. Also, in the event of toxicity problems removal is difficult.
Transdermal administration of drugs such as by patches, gels, pastes, or other known vehicles is not only convenient but for the most part painless, simple to apply and easy to remove during adverse reactions. Unfortunately, many drugs can not be applied in this manner because they do not cross the skin readily enough to give the desired efficacy. Unexpectedly it has been discovered that the class of gastric anti-secretory drugs, substituted 2-pyridylmethylthio- and sulfinyl-benzimidazoles and omeprazoles, can be administered transdermally and still effectively inhibit the enzyme responsible for gastric acid secretion.
INFORMATION DISCLOSURE
U.S. Pat. No. 4,575,554 discloses the oral and parenteral administration of substituted 2-pyridylmethylthio- and sulfinyl-benzimidazoles for the treatment of gastrointestinal diseases.
U.S. Pat. No. 4,255,431 discloses a method and composition including omeprazole for inhibiting gastric acid secretion.
SUMMARY OF THE INVENTION
The present invention is directed toward a method and transdermal composition for inhibiting the secretion of gastric acid for prevention or treatment of gastrointestinal disease comprising the application to the skin of a mammal, including humans, a therapeutically effective amount of a compound of formula I ##STR1## wherein X is
(a) ═S, or
(b) ═S→O;
R1 is
(a) hydrogen,
(b) methyl,
(c) methoxy, or
(d) trifluoromethyl;
R2 is
(a) methoxy, or
(b) --SR5 wherein R5 is (C1 -C4)alkyl, (C1 -C4)alkenyl, PhX, --CH2 PhX, or (C3 -C10)cycloalkyl, wherein "PhX" is phenyl substituted by zero to 3 of the following: (C1 -C4)alkyl, chloro, fluoro, bromo, nitro, trifluoromethyl, or OR3 ; and
R3 and R4 are the same or different and are
(a) hydrogen, or
(b) (C1 -C4)alkyl.
Generally the compounds are first dissolved in a transdermal cream, paste, gel or liquid or otherwise absorbed into a transdermal patch. Preferred compounds derived from Formula 1 are 2-(4-ethylthio-3-methylpyridin-2-yl methyl)sulfinyl-benzimidazole and omeprazole. Omeprazole is where X is ═S→O, R1 and R2 are methoxy and R3 and R4 are methyl.
The compound is dissolved in a transdermal vehicle in an amount of from about 1 to about 300 mg/dose. The dissolved compound can then be applied to the skin of a mammal, preferably a human being, to be absorbed through the skin such that the (H+ -K+) ATPase enzyme responsible for gastric acid secretion is inhibited.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the effective transdermal administration of substituted 2-pyridylmethylthio- and sulfinyl-benzimidazoles, omeprazole or a pharmaceutically acceptable salt thereof for inhibition of gastric acid secretion. The gastric acid secretion is controlled by inhibiting gastric (H+ -K+) ATPase activity.
The 2-pyridylmethylthio- and sulfinyl- benzimidazole compounds are described in U.S. Pat. No. 4,575,554 herein incorporated by reference. The omeprazole compound is described in U.S. Pat. No. 4,255,431 herein incorporated by reference. Generally these compounds are structurally represented by Formula I, shown above, wherein X is ═S, or ═S→O; R1 is hydrogen, methyl, methoxy, or trifluoromethyl; R2 is methoxy or --SR5 wherein R5 is (C1 -C4)alkyl, (C1 -C4)alkenyl, PhX, --CH2 PhX or (C3 -C10) cycloalkyl, wherein "PhX" is phenyl substituted by zero to 3 of the following: (C1 -C4)alkyl, chloro, fluoro, bromo, nitro, trifluoromethyl, or OR3 ; and R3 and R4 are the same or different and are hydrogen, or (C1 -C4)alkyl.
A preferred compound from this family is 2-(4-ethylthio-3-methylpyridin-2-yl methyl)sulfinyl-benzimidazole and omeprazole which is when X is ═S→O, R1 and R2 are methoxy and R3 and R4 are methyl.
The foregoing compounds are dissolved in a suitable transdermal vehicle such as a cream, gel, paste or liquid which are generally known in the art for transdermal use. Typical transdermal compounds are polyethylene glycol, propylene glycol, triacetin, propylcarbonate, ethanol and isopropyl myristate. The compounds can also be applied to porous or other material suitable for preparing a transdermal patch which can be worn by the patient. Such transdermal vehicles are generally well-known in the pharmaceutical industry and therefore will not be discussed in detail.
The compounds are transdermally applied in a therapeutically effective amount to inhibit gastric acid secretion. Generally the amount is from about 1 to about 300 mg/dosage, preferably about 100 to about 200 mg/dosage. However it is to be recognized that the amount used in the transdermal vehicle is greatly in excess of the amount actually transferred into the body. A typical cross-over rate is generally much less than the available drug present in the transdermal vehicle. The dosage is of course dependent upon the patient and diagnosed condition.
In order to prove the effectiveness of the transdermal administration, the subject compounds were dissolved in dimethyl sulfoxide (DMSO) and applied to the backs of rats and onto the ears of rabbits. The animals were allowed to rest for varying amounts of time and then the inhibition of (H+ -K+) ATPase, the enzyme responsible for gastric acid secretion, was measured. The results indicated that the compounds were absorbed such that (H+ -K+) ATPase was inhibited.
The following examples further describe and demonstrate the subject invention. For each of the following examples the drug dilutions were prepared in DMSO to a final concentration of 150 mg/ml. The drug was made fresh prior to each application.
The inhibition of (H+ -K+) ATPase activity was determined as described by Im, W. B.; Blalkeman, D. P., "Inhibitiion of Gastric pH+ -K+) ATPase by Unsaturated Long Chain Fatty Acids" Biochem. et Biophy. Acta 692:355-60 (1982). For the rat models, fundic gastric mucosal microsomes were prepared and (H+ -K+) ATPase activity in the microsomes was estimated by measuring K+ -dependent ATP-hydrolysis.
For the rabbit models, mucosa from the fundic region was removed by blunt dissection and minced with scissors. 2.5 g of the minced tissue was placed in 25 ml of buffer containing 250 mM sucrose, 2 mM MgCl2, 1 mM EGTA, and 2 mM Hepes/Tris, pH 7.4. The tissues were then prepared as described for the rat gastric mucosa.
EXAMPLE 1 Effect of Transdermal 2-(4-ethylthio-3-methylpyridin-2-yl methyl)sulfinyl-benzimidazole in Rats
Male, Upjohn Sprague Dawley rats were anesthetized with sodium pentobarbital and their dorsal hair removed with the depilatory NAIR. Care was taken to prevent abrasions which might result from hair removal. The animals were returned to their cages and allowed to recover for twenty-four hours. The rats were then fasted overnight in metal restraining tubes without water prior to treatment. 2-(4-ethylthio-3-methylpyridin-2-yl methyl)sulfinyl-benzimidazole at 0 or 100 mg/kg was applied to the backs of the rats and spread with an Eppendorf pipette tip. The same volume of DMSO alone was applied after 2 hrs to all animals. The rats were evaluated 5 or 30 hours after the initial dose for determination of (H+ -K+) ATPase activity.
Transdermal treatment with the subject compound reduced (H+ -K+) ATPase activity 60-65% from control. Activity did not change with time.
EXAMPLE 2 Effect of Transdermal Omeprazole in Rats
Male, Upjohn Sprague Dawley rats were anesthetized with sodium pentobarbital and their dorsal hair removed with the depilatory NAIR. Care was taken to prevent abrasions which might result from hair removal. The animals were returned to their cages and allowed to recover for twenty-four hours. The rats were then fasted overnight in metal restraining tubes without water prior to treatment. Omeprazole at 0 or 100 mg/kg was applied to the backs of the rats and spread with an Eppendorf pipette tip. The same volume of DMSO alone was applied after 2 hrs to all animals. The rats were evaluated 5 or 30 hours after the initial dose for determination of (H+ -K+) ATPase activity.
Transdermal treatment with omeprazole reduced (H+ -K+) ATPase activity 35% as compared to the control after 5 hours and 27% as compared to the control after 30 hours. Thus, demonstrating that the omeprazole was absorbed through the skin and inhibited (H+ -K+) ATPase activity.
EXAMPLE 3 Effect of Additional DMSO on Transdermal Activity
The rats were prepared as described in Example 1 and fasted overnight. The same compound as in Example 1 was applied at 0, 100 or 200 mg/kg. Additional volumes (100 μl) of DMSO were spread over the treatment area one time (after two hours) or four times (after one, two, three and four hours). The animals were evaluated 5 hours after the initial dose for determination of (H+ -K+) ATPase activity.
The transdermal treatment (100 mg/kg) reduced (H+ -K+) ATPase activity 65% from control. Additional applications of DMSO (four wipes) reduced the activity of the same dose an additional 16%. A 200 mg/kg dose with one wipe of DMSO after two hours reduced the (H+ -K+) ATPase activity by 72%. Thus, the additional applications of DMSO were more effective (81%) than a single application at twice the dosage (200 mg/kg).
EXAMPLE 4 Effect of Transdermal Applications in Rats: Dose Response
Rats were prepared as described in Example 1 and fasted overnight. The same compound as used in Example 1 was applied at 0, 25, 50, or 100 mg/kg. Additional volumes (100 μl) of DMSO were spread over the treatment area after 2, 5, and 7 hours. The animals were evaluated 24 hours after the initial dose for determination of (H+ -K+) ATPase activity.
The results showed approximately a 50% reduction in (H+ -K+) ATPase from the control indicating that the reduction in activity was at a maximum even at the lower dose. This suggests that a minimum of 4% of the lowest dose was absorbed.
EXAMPLE 5 Transdermal Activity in Rabbits
Male, New Zealand White rabbits were fasted overnight without water in their cages prior to treatment. The same compound as used in Example 1 was applied at 0 or 100 mg/kg in divided doses (1/2 to each ear) to naive rabbit ears. The rabbits received an additional application of DMSO to the treatment area after 1, 3, 5, 7, 24 and 25 hrs. The rabbits were evaluated 30 hrs after the initial dose for determination of (H+ -K+) ATPase activity.
The results showed that the transdermal treatment reduced (H+ -K+) ATPase activity 87% from control when applied to rabbit ears, no signs of irritation were observed.
The examples show that transdermal application of the subject compounds is effective for reducing (H+ -K+) ATPase activity. Also, the effect remains long lasting when applied and no signs of irritation were apparent.

Claims (10)

We claim:
1. A method for transdermally inhibiting the the secretion of gastric acid for prevention or treatment of gastrointestinal disease in mammals comprising: applying to the skin of a mammal a therapeutically effective amount of a compound of formula I ##STR2## or a pharmaceutically acceptable salt thereof wherein X is
(a) ═S, or
(b) ═S→O;
R1 is
(a) hydrogen,
(b) methyl,
(c) methoxy, or
(d) trifluoromethyl;
R2 is
(a) methoxy,
(b) --SR5 wherein R5 is (C1 -C4)alkyl, (C1 -C4)alkenyl, PhX, --CH2 PhX, or (C3 -C10)cycloalkyl, wherein (PhX) is phenyl substituted by zero to 3 of the following: (C1 -C4)alkyl, chloro, fluoro, bromo, nitro, trifluoromethyl, or OR3 ; and
R3 and R4 are the same or different and are
(a) hydrogen, or
(b) (C1 -C4)alkyl.
2. The method of claim 1 wherein said compound is first dissolved in a transdermal cream, paste, gel or liquid or otherwise absorbed into a transdermal patch.
3. The method of claim 1 wherein said compound is 2-(4-ethylthio-3-methylpyridin-2-yl methyl)sulfinyl-benzimidazole.
4. The method of claim wherein said compound is omeprazole, X is ═S→O, R1 and R2 are methoxy and R3 and R4 are methyl.
5. The method of claim 2 wherein said compound is dissolved in an amount of from about 1 to about 300 mg/dose.
6. A pharmaceutical composition comprising: a compound of formula I ##STR3## or a pharmaceutically acceptable salt thereof in a therapeutically effective amount; wherein
X is
(a) ═S, or
(b) ═S→O;
R1 is
(a) hydrogen,
(b) methyl,
(c) methoxy, or
(d) trifluoromethyl;
R2 is
(a) methoxy
(b) --SR5 wherein R5 is (C1 -C4)alkyl, (C1 -C4)alkenyl, PhX, --CH2 PhX, or (C3 -C10)cycloalkyl, wherein (PhX) is phenyl substituted by zero to 3 to the following: (C1 -C4)alkyl, chloro, fluoro, bromo, nitro, trifluoromethyl, or OR3 ; and
R3 and R4 are the same or different and are
(a) hydrogen, or
(b) (C1 -C4)alkyl; and a transdermal vehicle.
7. The pharmaceutical composition of claim 6 wherein said compound is 2-(4-ethylthio-3-methylpyridin-2-yl methyl)sulfinyl-benzimidazole.
8. The pharmaceutical composition of claim 6 wherein said compound is omeprazole, X is ═S→O, R1 and R2 are methoxy and R3 and R4 are methyl.
9. The pharmaceutical composition of claim 6 wherein said transdermal vehicle is a cream, paste, gel or liquid or otherwise absorbed into a transdermal patch.
10. The pharmaceutical composition of claim 6 wherein said compound is dissolved in said transdermal vehicle in an amount of from about 1 to about 300 mg/dose.
US07/623,884 1988-06-30 1989-05-01 Transdermal antisecretory agents for gastrointestinal disease Expired - Fee Related US5124158A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US21378688A 1988-06-30 1988-06-30

Publications (1)

Publication Number Publication Date
US5124158A true US5124158A (en) 1992-06-23

Family

ID=22796502

Family Applications (1)

Application Number Title Priority Date Filing Date
US07/623,884 Expired - Fee Related US5124158A (en) 1988-06-30 1989-05-01 Transdermal antisecretory agents for gastrointestinal disease

Country Status (6)

Country Link
US (1) US5124158A (en)
EP (1) EP0425505B1 (en)
JP (1) JPH03505450A (en)
AU (1) AU3683889A (en)
CA (1) CA1324758C (en)
WO (1) WO1990000054A1 (en)

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5333621A (en) * 1993-05-28 1994-08-02 Eric Denzer Condom with transdermal vasodilator
WO1996031213A1 (en) * 1995-04-04 1996-10-10 Merck & Co., Inc. Pharmaceutical composition containing proton pump inhibitors
US6007836A (en) * 1993-05-28 1999-12-28 Vericade, Inc. Transdermal vasodilator
US6262085B1 (en) 1999-08-26 2001-07-17 Robert R. Whittle Alkoxy substituted Benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
US6262086B1 (en) 1999-08-26 2001-07-17 Robert R. Whittle Pharmaceutical unit dosage form
US6268385B1 (en) 1999-08-26 2001-07-31 Robert R. Whittle Dry blend pharmaceutical formulations
US6312723B1 (en) 1999-08-26 2001-11-06 Robert R. Whittle Pharmaceutical unit dosage form
US6312712B1 (en) 1999-08-26 2001-11-06 Robert R. Whittle Method of improving bioavailability
US6316020B1 (en) 1999-08-26 2001-11-13 Robert R. Whittle Pharmaceutical formulations
US6326384B1 (en) 1999-08-26 2001-12-04 Robert R. Whittle Dry blend pharmaceutical unit dosage form
US6369087B1 (en) 1999-08-26 2002-04-09 Robert R. Whittle Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
US6489346B1 (en) 1996-01-04 2002-12-03 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US6645988B2 (en) 1996-01-04 2003-11-11 Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US20030211147A1 (en) * 2000-09-29 2003-11-13 Cullen Daniel J. Proton pump inhibitor formulation
US20030228363A1 (en) * 2002-06-07 2003-12-11 Patel Mahendra R. Stabilized pharmaceutical compositons containing benzimidazole compounds
US20040006111A1 (en) * 2002-01-25 2004-01-08 Kenneth Widder Transmucosal delivery of proton pump inhibitors
US6699885B2 (en) 1996-01-04 2004-03-02 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and methods of using same
US20040106713A1 (en) * 2002-12-03 2004-06-03 Avakian Roger W. Use of additives in compounds containing macrocyclic poly(alkylene dicarboxylate) oligomers
US6780880B1 (en) 1999-08-26 2004-08-24 Robert R. Whittle FT-Raman spectroscopic measurement
US20040248942A1 (en) * 2003-02-20 2004-12-09 Bonnie Hepburn Novel formulation, omeprazole antacid complex-immediate release for rapid and sustained suppression of gastric acid
US20050031700A1 (en) * 2003-07-18 2005-02-10 Sanatarus, Inc. Pharmaceutical formulation and method for treating acid-caused gastrointestinal disorders
US20050038096A1 (en) * 2003-08-13 2005-02-17 The University Of Houston Parenteral and oral formulations of benzimidazoles
US20050266071A1 (en) * 2004-05-25 2005-12-01 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US20060147522A1 (en) * 2004-05-25 2006-07-06 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US20060204585A1 (en) * 2003-07-18 2006-09-14 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US20070292498A1 (en) * 2003-11-05 2007-12-20 Warren Hall Combinations of proton pump inhibitors, sleep aids, buffers and pain relievers
US20080287502A1 (en) * 2004-03-30 2008-11-20 Dermatrends, Inc. Transdermal Administration of Proton Pump Inhibitors
US20090092658A1 (en) * 2007-10-05 2009-04-09 Santarus, Inc. Novel formulations of proton pump inhibitors and methods of using these formulations
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5725874A (en) * 1993-05-19 1998-03-10 Hisamitsu Pharmaceutical Co., Inc. Solubilizer and external preparations containing the same
US6174548B1 (en) 1998-08-28 2001-01-16 Andrx Pharmaceuticals, Inc. Omeprazole formulation
US6096340A (en) * 1997-11-14 2000-08-01 Andrx Pharmaceuticals, Inc. Omeprazole formulation
US6733778B1 (en) 1999-08-27 2004-05-11 Andrx Pharmaceuticals, Inc. Omeprazole formulation

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4255431A (en) * 1978-04-14 1981-03-10 Aktiebolaget Hassle Gastric acid secretion inhibiting substituted 2-(2-benzimidazolyl)-pyridines, pharmaceutical preparations containing same, and method for inhibiting gastric acid secretion
US4575554A (en) * 1983-12-05 1986-03-11 The Upjohn Company Substituted 2-pyridylmethylthio- and sulfinyl-benzimidazoles as gastric antisecretory agents
GB2191693A (en) * 1986-06-18 1987-12-23 Frederick Jacob Bloomfield Anti-inflammatory agents
US4743588A (en) * 1984-06-13 1988-05-10 Allergan Pharmaceuticals, Inc. Compositions and methods of enhancing transdermal and transmembrane penetration systemic agents
US4911916A (en) * 1986-12-22 1990-03-27 Cygnus Research Corporation Diffusion matrix for transdermal drug administration and transdermal drug delivery devices including same
US4915950A (en) * 1988-02-12 1990-04-10 Cygnus Research Corporation Printed transdermal drug delivery device

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4255431A (en) * 1978-04-14 1981-03-10 Aktiebolaget Hassle Gastric acid secretion inhibiting substituted 2-(2-benzimidazolyl)-pyridines, pharmaceutical preparations containing same, and method for inhibiting gastric acid secretion
US4575554A (en) * 1983-12-05 1986-03-11 The Upjohn Company Substituted 2-pyridylmethylthio- and sulfinyl-benzimidazoles as gastric antisecretory agents
US4743588A (en) * 1984-06-13 1988-05-10 Allergan Pharmaceuticals, Inc. Compositions and methods of enhancing transdermal and transmembrane penetration systemic agents
GB2191693A (en) * 1986-06-18 1987-12-23 Frederick Jacob Bloomfield Anti-inflammatory agents
US4911916A (en) * 1986-12-22 1990-03-27 Cygnus Research Corporation Diffusion matrix for transdermal drug administration and transdermal drug delivery devices including same
US4915950A (en) * 1988-02-12 1990-04-10 Cygnus Research Corporation Printed transdermal drug delivery device

Cited By (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6007836A (en) * 1993-05-28 1999-12-28 Vericade, Inc. Transdermal vasodilator
US5333621A (en) * 1993-05-28 1994-08-02 Eric Denzer Condom with transdermal vasodilator
CN1080119C (en) * 1995-04-04 2002-03-06 麦克公司 Pharmaceutical composition contg. proton pump inhititors
WO1996031213A1 (en) * 1995-04-04 1996-10-10 Merck & Co., Inc. Pharmaceutical composition containing proton pump inhibitors
US5708017A (en) * 1995-04-04 1998-01-13 Merck & Co., Inc. Stable, ready-to-use pharmaceutical paste composition containing proton pump inhibitors
US20050004171A1 (en) * 1996-01-04 2005-01-06 Phillips Jeffrey O. Novel substituted benzimidazole dosage forms and method of using same
US6645988B2 (en) 1996-01-04 2003-11-11 Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US20040171646A1 (en) * 1996-01-04 2004-09-02 The Curators Of The University Of Missouri Novel substituted benzimidazole dosage forms and method of using same
US6780882B2 (en) 1996-01-04 2004-08-24 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US20040048896A1 (en) * 1996-01-04 2004-03-11 Phillips Jeffrey Owen Novel substituted benzimidazole dosage forms and method of using same
US6699885B2 (en) 1996-01-04 2004-03-02 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and methods of using same
US20050042304A1 (en) * 1996-01-04 2005-02-24 Phillips Jeffrey Owen Novel substituted benzimidazole dosage forms and method of using same
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US20030215527A1 (en) * 1996-01-04 2003-11-20 Phillips Jeffrey Owen Novel substituted benzimidazole dosage forms and method of using same
US6489346B1 (en) 1996-01-04 2002-12-03 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US6369087B1 (en) 1999-08-26 2002-04-09 Robert R. Whittle Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
US6706737B2 (en) 1999-08-26 2004-03-16 Robert R. Whittle Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
US6444689B1 (en) 1999-08-26 2002-09-03 Robert R. Whittle Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
US6653329B1 (en) 1999-08-26 2003-11-25 Robert R. Whittle Granulated pharmaceutical formulations and methods for making the same
US20050176774A1 (en) * 1999-08-26 2005-08-11 Whittle Robert R. FT-Raman spectroscopic measurement
US6667321B2 (en) 1999-08-26 2003-12-23 Robert R. Whittle Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
US6667324B1 (en) 1999-08-26 2003-12-23 Robert R. Whittle Dry blend pharmaceutical formulations
US6667323B1 (en) 1999-08-26 2003-12-23 Robert R. Whittle Dry-blend pharmaceutical formulations
US6262085B1 (en) 1999-08-26 2001-07-17 Robert R. Whittle Alkoxy substituted Benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
US6326384B1 (en) 1999-08-26 2001-12-04 Robert R. Whittle Dry blend pharmaceutical unit dosage form
US6316020B1 (en) 1999-08-26 2001-11-13 Robert R. Whittle Pharmaceutical formulations
US6262086B1 (en) 1999-08-26 2001-07-17 Robert R. Whittle Pharmaceutical unit dosage form
US6268385B1 (en) 1999-08-26 2001-07-31 Robert R. Whittle Dry blend pharmaceutical formulations
US20040157887A1 (en) * 1999-08-26 2004-08-12 Whittle Robert R. Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
US6312712B1 (en) 1999-08-26 2001-11-06 Robert R. Whittle Method of improving bioavailability
US6780880B1 (en) 1999-08-26 2004-08-24 Robert R. Whittle FT-Raman spectroscopic measurement
US6312723B1 (en) 1999-08-26 2001-11-06 Robert R. Whittle Pharmaceutical unit dosage form
US20030211147A1 (en) * 2000-09-29 2003-11-13 Cullen Daniel J. Proton pump inhibitor formulation
US20040006111A1 (en) * 2002-01-25 2004-01-08 Kenneth Widder Transmucosal delivery of proton pump inhibitors
US20030228363A1 (en) * 2002-06-07 2003-12-11 Patel Mahendra R. Stabilized pharmaceutical compositons containing benzimidazole compounds
US20040106713A1 (en) * 2002-12-03 2004-06-03 Avakian Roger W. Use of additives in compounds containing macrocyclic poly(alkylene dicarboxylate) oligomers
US20040248942A1 (en) * 2003-02-20 2004-12-09 Bonnie Hepburn Novel formulation, omeprazole antacid complex-immediate release for rapid and sustained suppression of gastric acid
US20100297220A1 (en) * 2003-07-18 2010-11-25 Santarus, Inc Pharmaceutical Formulation And Method For Treating Acid-Caused Gastrointestinal Disorders
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US20060204585A1 (en) * 2003-07-18 2006-09-14 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US20050031700A1 (en) * 2003-07-18 2005-02-10 Sanatarus, Inc. Pharmaceutical formulation and method for treating acid-caused gastrointestinal disorders
US20050038096A1 (en) * 2003-08-13 2005-02-17 The University Of Houston Parenteral and oral formulations of benzimidazoles
WO2005018623A3 (en) * 2003-08-13 2007-09-27 Univ Houston Parenteral and oral formulations of benzimidazoles
US7419996B2 (en) 2003-08-13 2008-09-02 The University Of Houston Parenteral and oral formulations of benzimidazoles
US20070292498A1 (en) * 2003-11-05 2007-12-20 Warren Hall Combinations of proton pump inhibitors, sleep aids, buffers and pain relievers
US20080287502A1 (en) * 2004-03-30 2008-11-20 Dermatrends, Inc. Transdermal Administration of Proton Pump Inhibitors
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8815916B2 (en) 2004-05-25 2014-08-26 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US20050266071A1 (en) * 2004-05-25 2005-12-01 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US20060147522A1 (en) * 2004-05-25 2006-07-06 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US20090092658A1 (en) * 2007-10-05 2009-04-09 Santarus, Inc. Novel formulations of proton pump inhibitors and methods of using these formulations

Also Published As

Publication number Publication date
WO1990000054A1 (en) 1990-01-11
JPH03505450A (en) 1991-11-28
CA1324758C (en) 1993-11-30
EP0425505B1 (en) 1993-03-17
AU3683889A (en) 1990-01-23
EP0425505A1 (en) 1991-05-08

Similar Documents

Publication Publication Date Title
US5124158A (en) Transdermal antisecretory agents for gastrointestinal disease
KR960001373B1 (en) Penetration enhancement composition of binary system for
EP0436217B1 (en) Anti-inflammatory analgesic patch
KR0123932B1 (en) External anti-inflammatory and analgesic plaster preparation
EP0506658B1 (en) Compositions and method for treating painful, inflammatory or allergic disorders
PL213976B1 (en) Pharmaceutical composition
US4820711A (en) Method for treating actinic keratosis with cytotoxic agents
US4440778A (en) Anti-inflammatory analgesic cataplasm and process for producing the same
SK287249B6 (en) Medicinal products with cicatrizing action comprising biguanide derivatives
JPH07196516A (en) Therapeutic agent for hemorrhoids
CA1169774A (en) Medication having penetration through cutaneous surfaces into articular and muscular areas
US5036050A (en) Compositions containing thymopentin for topical treatment of skin disorders
JPH07557B2 (en) Composition for treating dermatitis
US5128375A (en) Keloid treating agent
JP3899267B2 (en) Use of tosylchloramide to treat skin, mucous membrane, organ or tissue disorders
EP0680760A1 (en) Topical antipruritic composition containing a phosphonic acid diester compound
KR20040081791A (en) Percutaneous preparations
JP4500013B2 (en) Local anesthetic composition
JP2000119186A (en) Sucralfate-containing pharmaceutical composition for local administration
EP1256346A1 (en) Remedies for external use for allergic skin diseases
DE68905479T2 (en) TRANSDERMATE LUBRICANT INGREDIENTS FOR THE TREATMENT OF GASTRONIC DISEASES.
WO2001003774A2 (en) Pharmaceutical composition for the treatment of calcification
SK141993A3 (en) Treatmental unguent without irritative reaction for skin and the method of its preparation
JP2506216B2 (en) Anti-inflammatory analgesic external preparation
EP0168626A1 (en) Composition for the manufacture of a medicament for the therapeutic treatment of trauma of the skin

Legal Events

Date Code Title Description
AS Assignment

Owner name: UPJOHN COMPANY, THE, KALAMAZOO, MICHIGAN A CORP. O

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:IM, WHA B.;REEL/FRAME:005579/0689

Effective date: 19890512

AS Assignment

Owner name: UPJOHN COMPANY, THE, KALAMAZOO, MICHIGAN A CORP. O

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:RUWART, MARY J.;REEL/FRAME:005579/0693

Effective date: 19890510

FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
FP Lapsed due to failure to pay maintenance fee

Effective date: 19960626

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362